The present invention relates to a method for delaying the onset of tolerance to opiates, and thereby inhibiting the development of tolerance to and dependence on opiates, without substantial alteration of their analgesic effects.
2. Description of the Prior Art
Opiates have been used for centuries to treat pain. The prototype of the analgesia-producing opiates is morphine. Morphine is a rapid and effective treatment for pain, but its long term use is limited due to negative side effects. Of these negative side effects tolerance and dependence are the hardest to counteract. Research in the areas of tolerance and addiction indicates that they are pharmacologically distinct components of opiate administration. These types of data suggest that tolerance, addiction/dependence and analgesia may be modulated by different neurochemical systems and/or different receptor subtypes.
5-Hydroxytryptamine, ("5-HT"), commonly known as serotonin, has been demonstrated to interact with the opiate system. Anatomically, fibers from the predominantly opiate periaquaductal gray region ("PAG") have been shown to connect with the serotonergic dorsal raphe region. In awake, behaving animals, 5-HT reuptake inhibitors are able to potentiate opiate analgesia. In humans, administration of tryptophan, the precursor of serotonin improves tolerance to the analgesia producing stimulation of the PAG.
Due to the advent of receptor binding techniques, several receptor subtypes for 5-HT have been identified. In particular, the 5-HT.sub.3 receptor subtype has been localized on pain transmitting primary afferent fibers. We thus chose to determine if the 5-HT.sub.3 receptor 1) modulates morphine analgesia and 2) modulates the onset of tolerance to morphine analgesia.
The 5-HT.sub.3 antagonist utilized herein are known compounds, having been previously described. European Pat. Appl. No. 099789 A.sub.1, for example, discloses a series of benzamides of which 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide (zacopride) is the most important as potent antiemetic. U.S. Pat. No. 4,820,715 to Monkovic et al, discloses the synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(butan-2-on-3-yl)oxy-5-chloroben zamide, (BMY 33462), and 4-amino-2-(butan-2-on-3-yl)oxy-5-chloro-n-[2-(diethylamino)ethyl]benzamide (batanopride).
PCT/GB87/00826, to Glazo, published Feb. 26, 1987, discloses the potential use for 5-HT.sub.3 antagonists in treatment or prevention of withdrawal syndrome. 5-HT.sub.3 antagonists are under study for treatment of chemotherapy and drug-induced nausea and emesis. They are also being studied as antimigrane, anxiolytic, and antipsychotic agents. More recently, 5-HT.sub.3 are being studied as cognition enhancers.